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首页> 外文期刊>Frontiers in Genetics >Drosophila Model for the Analysis of Genesis of LIM-kinase 1-Dependent Williams-Beuren Syndrome Cognitive Phenotypes: INDELs, Transposable Elements of the Tc1/Mariner Superfamily and MicroRNAs
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Drosophila Model for the Analysis of Genesis of LIM-kinase 1-Dependent Williams-Beuren Syndrome Cognitive Phenotypes: INDELs, Transposable Elements of the Tc1/Mariner Superfamily and MicroRNAs

机译：果蝇模型的LIM激酶1依赖Williams-Beuren综合征认知表型的成因分析：INDELs，Tc1 / Mariner超家族的转座因子和MicroRNA。

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Genomic disorders, the syndromes with multiple manifestations, may occur sporadically due to unequal recombination in chromosomal regions with specific architecture. Therefore, each patient may carry an individual structural variant of DNA sequence (SV) with small insertions and deletions (INDELs) sometimes less than 10 bp. The transposable elements of the Tc1/mariner superfamily are often associated with hotspots for homologous recombination involved in human genetic disorders, such as Williams Beuren Syndromes (WBS) with LIM-kinase 1-dependent cognitive defects. The Drosophila melanogaster mutant agnts3 has unusual architecture of the agnostic locus harboring LIMK1: it is a hotspot of chromosome breaks, ectopic contacts, underreplication, and recombination. Here, we present the analysis of LIMK1-containing locus sequencing data in agnts3 and three D. melanogaster wild-type strains—Canton-S, Berlin, and Oregon-R. We found multiple strain-specific SVs, namely, single base changes and small INDEls. The specific feature of agnts3 is 28 bp A/T-rich insertion in intron 1 of LIMK1 and the insertion of mobile S-element from Tc1/mariner superfamily residing ~460 bp downstream LIMK1 3′UTR. Neither of SVs leads to amino acid substitutions in agnts3 LIMK1. However, they apparently affect the nucleosome distribution, non-canonical DNA structure formation and transcriptional factors binding. Interestingly, the overall expression of miRNAs including the biomarkers for human neurological diseases, is drastically reduced in agnts3 relative to the wild-type strains. Thus, LIMK1 DNA structure per se, as well as the pronounced changes in total miRNAs profile, probably lead to LIMK1 dysregulation and complex behavioral dysfunctions observed in agnts3 making this mutant a simple plausible Drosophila model for WBS.
机译：由于具有特定结构的染色体区域中的重组不均等，基因组疾病（具有多种表现的综合症）可能偶尔发生。因此，每位患者可能携带单个DNA序列（SV）的结构变异体，插入和缺失（INDELs）有时小于10 bp。 Tc1 / mariner超家族的转座因子通常与涉及人类遗传疾病的同源重组热点相关，例如具有LIM激酶1依赖性认知缺陷的Williams Beuren综合征（WBS）。果蝇果蝇突变体agnts3具有包含LIMK1的不可知基因座的异常结构：它是染色体断裂，异位接触，复制不足和重组的热点。在这里，我们介绍了agnts3和三个D. melanogaster野生型菌株（Canton-S，Berlin和Oregon-R）中包含LIMK1的基因座测序数据的分析。我们发现了多个应变特异的SV，即单碱基变化和小的INDEl。 agnts3的具体特征是LIMK1的内含子1中富含28 bp的A / T插入，以及来自Tc1 / mariner超家族的流动S元素的插入，位于下游LIMK1 3'UTR的约460 bp。 SV均未导致agnts3 LIMK1中的氨基酸取代。但是，它们显然会影响核小体的分布，非规范的DNA结构形成和转录因子的结合。有趣的是，与野生型菌株相比，在agnts3中，包括人类神经系统疾病生物标志物在内的miRNA的总体表达急剧下降。因此，LIMK1 DNA结构本身以及总miRNA谱中的明显变化，很可能导致在agnts3中观察到LIMK1失调和复杂的行为障碍，从而使该突变体成为WBS的简单合理的果蝇模型。

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